A new study from the University of Sydney has revealed how type 2 diabetes directly alters the heart's structure and energy systems, offering vital insights into why people with diabetes are at greater risk of heart failure.
Published in EMBO Molecular Medicine , the research was led by Dr Benjamin Hunter and Associate Professor Sean Lal from the School of Medical Sciences . The researchers analysed donated human heart tissue from patients undergoing heart transplantation in Sydney and found that diabetes causes distinct molecular changes to heart cells and structural changes to the muscle, especially in patients with ischaemic cardiomyopathy, the most common cause of heart failure.
"We've long seen a correlation between heart disease and type 2 diabetes," said Dr Hunter, "but this is the first research to jointly look at diabetes and ischaemic heart disease and uncover a unique molecular profile in people with both conditions.
"Our findings show that diabetes alters how the heart produces energy, maintains its structure under stress, and contracts to pump blood. Using advanced microscopy techniques, we were able to see direct changes to the heart muscle as a result of this, in the form of a build-up of fibrous tissue."
Heart disease is the leading cause of death in Australia and over 1.2 million people live with type 2 diabetes.
Associate Professor Lal said: "Our research links heart disease and diabetes in ways that have never been demonstrated in humans, offering new insights into potential treatment strategies that could one day benefit millions of people in Australia and globally."
Getting to the heart of the problem
The researchers examined heart tissue from transplant recipients and healthy donors.
The study discovered that diabetes is not just a co-morbidity for heart disease - it actively worsens heart failure by disrupting key biological processes and reshapes the heart muscle at a microscopic level.
"The metabolic effect of diabetes in the heart is not fully understood in humans," said Dr Hunter.
"Under healthy conditions, the heart primarily uses fats but also glucose and ketones as fuel for energy. It has previously been described that glucose uptake is increased in heart failure, however, diabetes reduces the insulin sensitivity of glucose transporters - proteins that move glucose in and out of cells - in heart muscle cells.
"We observed that diabetes worsens the molecular characteristics of heart failure in patients with advanced heart disease and increases the stress on mitochondria - the powerhouse of the cell which produces energy."
The researchers also observed reduced production of structural proteins critical for heart muscle contraction and calcium handling in people with diabetes and ischaemic heart disease, along with a build-up of tough, fibrous heart tissue that further affects the heart's ability to pump blood.
"RNA sequencing confirmed that many of these protein changes were also reflected at the gene transcription level, particularly in pathways related to energy metabolism and tissue structure, which reinforces our other observations," said Dr Hunter.
"And once we had these clues at the molecular level, we were able to confirm these structural changes using confocal microscopy."
Associate Professor Lal said the discovery of mitochondrial dysfunction and fibrotic pathways could help guide future therapies.
"Now that we've linked diabetes and heart disease at the molecular level and observed how it changes energy production in the heart while also changing its structure, we can begin to explore new treatment avenues," said Associate Professor Lal.
"Our findings could also be used to inform diagnosis criteria and disease management strategies across cardiology and endocrinology, improving care for millions of patients."
Research
Hunter B, Lal S, et al, ' Left ventricular myocardial molecular profile of human diabetic ischaemic cardiomyopathy ,' EMBO Molecular Medicine, August 2025.
DOI: 10.1038/s44321-025-00281-9
Declaration
This work was funded by the R.T. Hall Trust (RQ112) and philanthropic donations to the University of Sydney. This work was also supported by the National Health and Medical Research Council (NHMRC) of Australia and the National Heart Foundation (NHF) of Australia. The authors thank the patients and staff of St. Vincent's Hospital Sydney. The authors declare no conflict of financial or non-financial interests.
Diabetes reshapes the heart muscle at a microscopic level.
